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Grand Rapids, MI, United States

Sia A.T.,Research Center | Sng B.L.,Research Center | Lim E.C.,Research Center | Law H.,Genetic Services | Tan E.C.,Research Center
International Journal of Obstetric Anesthesia | Year: 2010

Background: Polymorphisms of the ATP-binding cassette sub-family B member -1 (ABCB1) gene that codes for P-glycoprotein could influence the efflux of morphine from the central nervous system affecting its analgesic action. We investigated the effect of ABCB1 gene polymorphisms on analgesia and the development of persistent pain in post caesarean patients. Methods: Women of Chinese descent who received spinal anaesthesia with intrathecal morphine for elective caesarean section were recruited. They were given intravenous morphine via a patient-controlled analgesia pump for postoperative analgesia. Blood samples were collected and analysed for the presence of C1236T, G2677T/A and C3435T single nucleotide polymorphisms of the ABCB1 gene. We primarily investigated the association between ABCB1 polymorphisms and the effect of morphine. In a postpartum phone survey of the subjects six months after surgery, the occurrence of persistent abdominal wound scar pain was established. Results: We found no significant statistical difference in total morphine consumption, pain scores and side effects among the various genotypes. For C3435T polymorphism, there was a trend towards the association of the T allele and persistent pain for three months after surgery but this did not reach statistical significance (P = 0.07). The TT genotype had the longest mean survival time of wound pain in comparison with CT and CC genotypes (P = 0.004 and P = 0.014, respectively). Conclusion: Polymorphisms of ABCB1 were not associated with differences in morphine use in the first 24 h after surgery. Women with the T allele of C3435T polymorphism showed a trend towards a higher risk of developing persistent postoperative pain. © 2010 Elsevier Ltd. Source

Guzauskas G.F.,University of Washington | Garrison L.P.,University of Washington | Stock J.,Seattle Childrens Center for Children with Special Needs | Au S.,Genetics Program | And 2 more authors.
Genetics in Medicine | Year: 2013

Purpose:Genetic services policymakers and insurers often make coverage decisions in the absence of complete evidence of clinical utility and under budget constraints. We evaluated genetic services stakeholder opinions on the potential usefulness of decision-Analytic modeling to inform coverage decisions, and asked them to identify genetic tests for decision-Analytic modeling studies.Methods:We presented an overview of decision-Analytic modeling to members of the Western States Genetic Services Collaborative Reimbursement Work Group and state Medicaid representatives and conducted directed content analysis and an anonymous survey to gauge their attitudes toward decision-Analytic modeling. Participants also identified and prioritized genetic services for prospective decision-Analytic evaluation.Results:Participants expressed dissatisfaction with current processes for evaluating insurance coverage of genetic services. Some participants expressed uncertainty about their comprehension of decision-Analytic modeling techniques. All stakeholders reported openness to using decision-Analytic modeling for genetic services assessments. Participants were most interested in application of decision-Analytic concepts to multiple-disorder testing platforms, such as next-generation sequencing and chromosomal microarray.Conclusion:Decision- Analytic modeling approaches may provide a useful decision tool to genetic services stakeholders and Medicaid decision-makers.Genet Med 2013:15(1):84-87. © American College of Medical Genetics and Genomics. Source

Kaiser F.J.,University of Lubeck | Ansari M.,University of Edinburgh | Braunholz D.,University of Lubeck | Gil-Rodriguez M.C.,University of Lubeck | And 80 more authors.
Human Molecular Genetics | Year: 2014

Cornelia de Lange syndrome (CdLS) is amultisystemgenetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ̃5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA.Wealso identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS. © The Author 2014. Published by Oxford University Press. All rights reserved.Published by Oxford University Press. All rights reserved. Source

Brett M.,Research Center | McPherson J.,National University of Singapore | Zang Z.J.,National Cancer Center | Lai A.,Genetic Services | And 8 more authors.
PLoS ONE | Year: 2014

Developmental delay and/or intellectual disability (DD/ID) affects 1-3% of all children. At least half of these are thought to have a genetic etiology. Recent studies have shown that massively parallel sequencing (MPS) using a targeted gene panel is particularly suited for diagnostic testing for genetically heterogeneous conditions. We report on our experiences with using massively parallel sequencing of a targeted gene panel of 355 genes for investigating the genetic etiology of eight patients with a wide range of phenotypes including DD/ID, congenital anomalies and/or autism spectrum disorder. Targeted sequence enrichment was performed using the Agilent SureSelect Target Enrichment Kit and sequenced on the Illumina HiSeq2000 using paired-end reads. For all eight patients, 81-84% of the targeted regions achieved read depths of at least 20×, with average read depths overlapping targets ranging from 322 × to 798 ×. Causative variants were successfully identified in two of the eight patients: a nonsense mutation in the ATRX gene and a canonical splice site mutation in the L1CAM gene. In a third patient, a canonical splice site variant in the USP9X gene could likely explain all or some of her clinical phenotypes. These results confirm the value of targeted MPS for investigating DD/ID in children for diagnostic purposes. However, targeted gene MPS was less likely to provide a genetic diagnosis for children whose phenotype includes autism. © 2014 Brett et al. Source

Toriello H.V.,Genetic Services | Toriello H.V.,Michigan State University | Erick M.,Brigham and Womens Hospital | Alessandri J.-L.,CHU de la Reunion | And 16 more authors.
American Journal of Medical Genetics, Part A | Year: 2013

Chondrodysplasia punctata (CDP) is an etiologically heterogeneous disorder characterized by the radiographic finding of stippled epiphyses (punctate calcifications). It is often accompanied by a characteristic facial appearance, known as the Binder phenotype, which is attributed to hypoplasia of the nasal cartilages; abnormal distal phalanges (brachytelephalangy) are a common component manifestation as well. We report eight patients with a Binder phenotype with or without CDP who all shared a known or suspected maternal deficiency of vitamin K. We suspect that this phenotype is probably under recognized, and we hope to increase awareness about the maternal risk factors, especially hyperemesis gravidarum, which lead to nutritional deficiency. © 2013 Wiley Periodicals, Inc. Source

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